Many patients with chronic myeloid leukemia (CML) attain excellent responses on imatinib (Gleevec). However, recurrence is the rule upon drug discontinuation, consistent with survival of fully leukemogenic CML progenitor cells in the presence of drug. Therefore, therapy must continue lifelong, often despite significant side effects. It is not well understood why CML progenitor cells survive in patients on imatinib, and therefore It is difficult to develop specific approaches to eradicate residual leukemia. The long-term objective of this project is to improve the prognosis and quality of life of CML patients, by understanding the mechanisms underlying the survival of CML progenitor cells during therapy. We have preliminary data suggesfing that CML progenitor cells can use alternative signals to compensate forthe loss of BCR-ABL acfivity upon treatment with BCR-ABL kinase inhibitors. Further we have evidence that inhibition ofthe stem cell factor recptor KIT Is a critical mediator of imatinib effcts on CML cells. Lastly, we have identified a gene expression signature associated with primary cytogenetic resistance to imatinib and have evidence that betacatenin may be involved in the regulation ofthe signature genes. We propose three Specific Aims: AIM 1. To elucidate mechanisms of CML progenitor cell survival upon inhibition of BCR-ABL .We will assess whether CML progenitor cells are dependent on BCR-ABL or whether JAK2-dependent stroma cellderived factors can protect them from the effects of BCR-ABL inhibitors. AIM 2. To determine the role of KIT for CML progenitor cell survival upon inhibition of BCR-ABL. We will test whether inhibifion of KIT is essential for the biological effects of imatinib on CML progenitor cells and whether KIT is required for BCR-ABL to induce CML. AIM 3. To determine the role of p-catenin for imatinib resistance. We will determine whether betacatenin is a master regulator of genes associated with primary imatinib failure, whether beta-catenin acfivafion confers imatinib resistance, and how beta-catenin is regulated in CML progenitor cells.